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Title:
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BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
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Author:
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Grotsky, David A.; González-Suárez, Ignacio; Novell Álvarez, Anna; Neumann, Martin; Yaddanapudi, Sree C.; Croke, Monica; Martínez Alonso, Montserrat; Redwood, Abena B.; Ortega-Martinez, Sylvia; Feng, Zhihui; Lerma, Enrique; Ramon y Cajal, Teresa; Zhang, Junran; Matias-Guiu, Xavier; Dusso Rosso, Adriana; Gonzalo, Susana
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Notes:
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Loss of 53BP1 rescues BRCA1 deficiency and is associated
with BRCA1-deficient and triple-negative
breast cancers (TNBC) and with resistance to genotoxic
drugs. The mechanisms responsible for decreased
53BP1 transcript and protein levels in tumors remain unknown.
Here, we demonstrate that BRCA1 loss activates
cathepsin L (CTSL)–mediated degradation of 53BP1. Activation
of this pathway rescued homologous recombination
repair and allowed BRCA1-deficient cells to bypass
growth arrest. Importantly, depletion or inhibition of CTSL
with vitamin D or specific inhibitors stabilized 53BP1 and
increased genomic instability in response to radiation
and poly(adenosine diphosphate–ribose) polymerase inhibitors,
compromising proliferation. Analysis of human
breast tumors identified nuclear CTSL as a positive biomarker
for TNBC, which correlated inversely with 53BP1.
Importantly, nuclear levels of CTSL, vitamin D receptor,
and 53BP1 emerged as a novel triple biomarker signature
for stratification of patients with BRCA1-mutated tumors
and TNBC, with potential predictive value for drug response.
We identify here a novel pathway with prospective
relevance for diagnosis and customization of breast
cancer therapy. |
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Rights:
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cc-by-nc-sa, (c) Grotsky et al., 2013
http://creativecommons.org/licenses/by-nc-sa/3.0/es/
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Document type:
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article
publishedVersion |
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Published by:
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The Rockefeller University Press
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